Foldamer helix bundle-based molecular encapsulation

Abstract

The present description provides compositions and methods for producing therapeutic oligomeric compounds. In another aspect the description provides methods for administering the oligomeric compounds for the treatment and prevention of disease in a mammal. In particular, the disclosure relates to medicaments comprising various novel oligomeric compounds and pharmaceutically acceptable salts thereof. The compounds of the disclosure may optionally be administered with at least one of a pharmaceutically acceptable excipient, additional pharmacologically active agent or a combination thereof.

The invention claimed is: 
     
       1. A compound comprising
 multiple non-peptide oligourea helical foldamers having a structure of at least one of: 
 an aliphatic non-peptide oligourea helical foldamer; 
 a short amphiphilic α-helicomimetic foldamer with proteinaceous side-chains; and a non-peptide oligourea peptidomimetic residue sequence selected from the group consisting of: 
 
       
         
           
                 
                 
                 
               
                     
                   (i)  
                   Leu u  Glu u  Lvs u  Leu u  Tvr u  Leu u    
                 
                     
                     
                   Glu u  Lvs u  Leu u  Ala u  Leu u  (H1); 
                 
                     
                   (ii)  
                   Leu u  Glu u  Leu u  Lvs u  Pro u  Leu u  Glu u    
                 
                     
                     
                   Leu u  Lvs u  Ala u  (H2); 
                 
                     
                   (iii)   
                   Leu u  Glu u  Lvs u  Leu u  Tvr u  Asn u  Glu u   
                 
                     
                     
                   Lvs u  Leu u  Ala u  Leu u  (H3); 
                 
                     
                   (iv)   
                   Ser u  Glu u  Lvs u  Leu u  Tvr u  Leu u  Glu u   
                 
                     
                     
                   Lvs u  Leu u  Ala u  Leu u  (H4); 
                 
                     
                   and 
                     
                 
                     
                   (v)  
                   Ala u  Leu u  Lvs u  Leu u  Glu u  Tvr u  Leu u  Glu u    
                 
                     
                     
                   Leu u  Lvs u  Ala u  Leu u  (H5), 
                 
             
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein the oligourea helical foldamers self-assemble to form at least one of an internal cavity, a pH-responsive water-filled channel with controllable pore diameter, a pH-responsive superhelical water-filled channel within a hydrophobic core, or a combination thereof. 
       
     
     
       2. The compound of  claim 1 , wherein the agent has an atomic mass less than about 1500 Da. 
     
     
       3. The compound of  claim 1 , wherein the oligourea helical foldamers self-assemble into their three-dimensional nanostructure in aqueous conditions. 
     
     
       4. The compound of  claim 1 , wherein at least one of:
 the compound has a secondary structure similar to a native peptide; 
 the compound is biologically active; 
 the compound further comprises a peptide that is fused to, contiguous with, or conjugated to the oligourea helical foldamer; or 
 a combination thereof. 
 
     
     
       5. The compound of  claim 4 , wherein the secondary structure acts as a receptor ligand, an effector molecule, an agonist, an antagonist, a modulator of protein-protein interactions, an organocatalyst, or an enzyme. 
     
     
       6. The compound of  claim 5 , wherein the peptide segment comprises an amino acid sequence corresponding to a biologically active peptide or a fragment thereof. 
     
     
       7. The compound of  claim 6 , wherein the peptide is a peptide a-helix. 
     
     
       8. The compound of  claim 7 , wherein the peptide a-helix includes an epitope that recognizes another compound. 
     
     
       9. The compound of  claim 8 , wherein the epitope acts as a receptor ligand, an effector molecule, an agonist, an antagonist, a modulator of protein-protein interactions, an organocatalyst, or an enzyme. 
     
     
       10. The compound of  claim 1 , wherein at least one of:
 the oligourea helical foldamer encapsulates a drug or substrate; 
 the oligourea helical foldamer transfers substances across a membrane; 
 the oligourea helical foldamer has an internal cavity with a volume in a range of about 400-600 Å 3 ; or 
 a combination thereof. 
 
     
     
       11. A composition comprising:
 an oligourea helical bundle comprising a non-peptide oligourea helical foldamer; and 
 an agent at least partially encapsulated by the oligourea helical bundle. 
 
     
     
       12. The composition of  claim 11 , wherein the agent has an atomic mass less than about 600 Da. 
     
     
       13. A therapeutic composition comprising an effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
       14. A peptide-oligourea chimeric compound, comprising:
 a peptide; and 
 an oligourea helical bundle comprising a non-peptide oligourea helical foldamer that is at least partially encapsulating an agent. 
 
     
     
       15. The peptide-oligourea chimeric compound of  claim 14 , wherein the agent has an atomic mass less than about 600 Da. 
     
     
       16. The compound of  claim 14 , wherein the oligourea helical foldamer self-assembles into its three-dimensional nanostructure under aqueous conditions. 
     
     
       17. The compound of  claim 14 , wherein the peptide is a peptide a-helix. 
     
     
       18. The compound of  claim 14 , wherein at least one of:
 the non-peptide oligourea helical foldamer includes aliphatic oligoureas; 
 the non-peptide oligourea helical foldamer is a short amphiphilic a-helicomimetic foldamer with proteinaceous side-chains; 
 the oligourea helical bundle has a non-peptide oligourea peptidomimetic residue sequence selected from the group consisting of: 
 
       
         
           
                 
                 
               
                   Leu u  Glu u  Lys u  Leu u  Tyr u  Leu u  Glu u  Lys u  Leu u  Ala u  Leu u  (H1); 
                     
                 
                     
                 
                   Leu u  Glu u  Leu u  Lys u  Pro u  Leu u  Glu u  Leu u  Lys u  Ala u  (H2); 
                 
                     
                 
                   Leu u  Glu u  Lys u  Leu u  Tyr u  Asn u  Glu u  Lys u  Leu u  Ala u  Leu u  (H3) 
                 
                     
                 
                   Ser u  Glu u  Lys u  Leu u  Tyr u  Leu u  Glu u  Lys u  Leu u  Ala u  Leu u  (H4); 
                 
                   and 
                 
                     
                 
                   Ala u  Leu u  Lys u  Leu u  Glu u  Tyr u  Leu u  Glu u  Leu u  Lys u  Ala u  Leu u  (H5); 
                 
             
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         the non-peptide oligourea helical foldamer has a non-peptide oligourea peptidomimetic residue sequence selected from the group consisting of: 
       
       
         
           
                 
                 
               
                   Leu u  Glu u  Lys u  Leu u  Tyr u  Leu u  Glu u  Lys u  Leu u  Ala u  Leu u  (H1); 
                     
                 
                     
                 
                   Leu u  Glu u  Leu u  Lys u  Pro u  Leu u  Glu u  Leu u  Lys u  Ala u  (H2); 
                 
                     
                 
                   Leu u  Glu u  Lys u  Leu u  Tyr u  Asn u  Glu u  Lys u  Leu u  Ala u  Leu u  (H3) 
                 
                     
                 
                   Ser u  Glu u  Lys u  Leu u  Tyr u  Leu u  Glu u  Lys u  Leu u  Ala u  Leu u  (H4); 
                 
                   and 
                 
                     
                 
                   Ala u  Leu u  Lys u  Leu u  Glu u  Tyr u  Leu u  Glu u  Leu u  Lys u  Ala u  Leu u  (H5); 
                 
             
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       and
 the oligourea helical bundle has an isolated cavity, a pH-responsive water-filled channels with controllable pore diameters or a pH-responsive superhelical channel with water-filled pores within the hydrophobic core of the bundle; or 
 a combination thereof. 
 
     
     
       19. The compound of  claim 14 , wherein the oligourea helical bundle has an internal cavity with a volume in a range of about 400-600 Å 3 . 
     
     
       20. A method of delivering an agent for the treatment or prevention of a disease or disorder, the method comprising administering to an individual in need thereof an effective amount of the composition of  claim 11 , wherein the agent is a therapeutic agent effective in ameliorating the disease or disorder. 
     
     
       21. A therapeutic composition comprising an effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
       22. A method of synthesizing a oligourea compound comprising the steps of:
 fabricating under aqueous conditions, a oligourea helical bundle with a non-peptide oligourea peptidomimetic residue sequence selected from the group consisting of:
 a helical pentad repeat (a, b, c, d, e):
 oligourea peptidomimetic residues with a hydrophobic side chain in positions a and d (e.g., Leu u ); 
 oligourea peptidomimetic residues with a charged residue in position b and c (e.g. Glu u  and Lys u , respectively); and 
 Tyr u  and Ala u  in position e; 
 
 a helical pentad repeat (a, b, c, d, e):
 oligourea peptidomimetic residues with a hydrophobic side chain in positions a and c (e.g. Leu u ); 
 oligourea peptidomimetic residues with a hydrophobic side chain in position e (e.g., Ala u  and Pro u  residues at the e position); and 
 oligourea peptidomimetic residues with a charged side chain in positions b and d (e.g., Glu u  and Lys u , respectively); 
 
 
 
       
         
           
                 
                 
               
                   Leu u  Glu u  Lys u  Leu u  Tyr u  Leu u  Glu u  Lys u  Leu u  Ala u  Leu u  (H1); 
                     
                 
                     
                 
                   Leu u  Glu u  Leu u  Lys u  Pro u  Leu u  Glu u  Leu u  Lys u  Ala u  (H2); 
                 
                     
                 
                   Leu u  Glu u  Lys u  Leu u  Tyr u  Asn u  Glu u  Lys u  Leu u  Ala u  Leu u  (H3) 
                 
                     
                 
                   Ser u  Glu u  Lys u  Leu u  Tyr u  Leu u  Glu u  Lys u  Leu u  Ala u  Leu u  (H4); or 
                 
                     
                 
                   Ala u  Leu u  Lys u  Leu u  Glu u  Tyr u  Leu u  Glu u  Leu u  Lys u  Ala u  Leu u  (H5); 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       and
 providing an agent while the oligourea helical bundle is self-assembling. 
 
     
     
       23. The method of  claim 22 , wherein the agent has an atomic mass less than about 600 Da. 
     
     
       24. The compound of  claim 11 , wherein:
 the non-peptide oligourea helical foldamer includes aliphatic oligoureas; the non-peptide oligourea helical foldamer is a short amphiphilic a-helicomimetic foldamer with proteinaceous side-chains; 
 the oligourea helical bundle has a non-peptide oligourea peptidomimetic residue sequence selected from the group consisting of: 
 
       
         
           
                 
               
                   (i) Leu u  Glu u  Lvs u  Leu u  Tvr u  Leu u  Glu u  Lvs u  Leu u  Ala u    
                 
                     
                 
                   Leu u  (H1); 
                 
                     
                 
                   (ii) Leu u  Glu u  Leu u  Lvs u  Pro u  Leu u  Glu u  Leu u  Lvs u  Ala u    
                 
                     
                 
                   (H2); 
                 
                     
                 
                   (iii) Leu u  Glu u  Lvs u  Leu u  Tvr u  Asn u  Glu u  Lvs u  Leu u  Ala u   
                 
                      
                 
                   Leu u  (H3); 
                 
                     
                 
                   (iv) Ser u  Glu u  Lvs u  Leu u  Tvr u  Leu u  Glu u  Lvs u  Leu u  Ala u    
                 
                     
                 
                   Leu u  (H4); 
                 
                   and 
                 
                     
                 
                   (v) Ala u  Leu u  Lvs u  Leu u  Glu u  Tvr u  Leu u  Glu u  Leu u  Lvs u   
                 
                       
                 
                   Ala u  Leu u  (H5), 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         the non-peptide oligourea helical foldamer has a non-peptide oligourea peptidomimetic residue sequence selected from the group consisting of: 
       
       
         
           
                 
               
                   (i) Leu u  Glu u  Lvs u  Leu u  Tvr u  Leu u  Glu u  Lvs u  Leu u  Ala u    
                 
                     
                 
                   Leu u  (H1); 
                 
                     
                 
                   (ii) Leu u  Glu u  Leu u  Lvs u  Pro u  Leu u  Glu u  Leu u  Lvs u  Ala u    
                 
                     
                 
                   (H2); 
                 
                     
                 
                   (iii) Leu u  Glu u  Lvs u  Leu u  Tvr u  Asn u  Glu u  Lvs u  Leu u  Ala u   
                 
                      
                 
                   Leu u  (H3); 
                 
                     
                 
                   (iv) Ser u  Glu u  Lvs u  Leu u  Tvr u  Leu u  Glu u  Lvs u  Leu u  Ala u    
                 
                     
                 
                   Leu u  (H4); 
                 
                   and 
                 
                     
                 
                   (v) Ala u  Leu u  Lvs u  Leu u  Glu u  Tvr u  Leu u  Glu u  Leu u  Lvs u   
                 
                       
                 
                   Ala u  Leu u  (H5), 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         and the oligourea helical bundle has an isolated cavity, a pH-responsive water-filled channels with controllable pore diameters or a pH-responsive superhelical channel with water-filled pores within the hydrophobic core of the bundle.